SUCHAROSE OCTASULFATE FOR USE IN INCREASE SKIN OXYGEN ENSURE IN THE TREATMENT OF ISCHEMIC WOUNDS

Description

[0001] The present invention relates to a synthetic polysulfated oligosaccharide having 1 to 4 monosaccharide units, its salts, or its complexes, for its use in increasing skin oxygenation during the treatment of grade 2 and / or 3 ischemic wounds, ie the healing of ischemic wounds, said oligosaccharide being sucrose octasulfate. Background to the invention

[0002] Wound healing is a natural biological phenomenon, with mammalian tissues capable of repairing localized lesions through their own repair and regeneration processes.

[0003] The speed and quality of wound healing depend on the general condition of the affected organism, the etiology of the wound, the condition and location of the wound, and the occurrence or absence of infection, as well as genetic factors predisposing or not to healing disorders.

[0004] Natural wound healing occurs primarily in three successive phases, each of which is characterized by specific cellular activities that advance the repair process in precise chronological sequences: the inflammatory phase, the granulation phase (or proliferative phase), and the maturation phase.

[0005] The first phase, the inflammatory phase, begins as soon as the blood vessels rupture, which triggers the formation of a clot (blood coagulation) mainly composed of fibrin and fibronectin, and which will constitute a temporary matrix. This matrix partially fills the lesion and will allow the migration within the injured area of ​​inflammatory cells recruited to ensure the debridement of the wound. The platelets present will also release factors (for example cytokine, growth factors) allowing the recruitment of healing cells such as inflammatory cells (neutrophils and macrophages), fibroblasts and endothelial cells.

[0006] The second phase corresponds to the development of granulation tissue. First, colonization of the wound by proliferation of fibroblasts is observed. Then, the migration of endothelial cells from healthy vessels will allow the formation of new blood vessels (neovascularization), or angiogenesis, of the injured tissue. This stage of angiogenesis is fundamental to initiate healing. In the granulation tissue, fibroblasts are activated and will differentiate into myofibroblasts with significant contractile properties, generated by actin microfilaments, allowing contraction of the wound.

[0007] The third phase of the repair process, maturation, is accompanied by remodeling of the granulation tissue. Part of the extracellular matrix is ​​digested by proteases (mainly matrix metalloproteases (MMPs) and elastases), and a progressive reorganization of the extracellular matrix is ​​observed. Gradually, type III collagen, the majority in granulation tissue, is replaced by type I collagen, the main matrix component of the dermis. At the end of the maturation phase, fibroblasts, myofibroblasts, and vascular cells experience reduced proliferation and / or activity. Then, excess cells die by apoptosis. In parallel with the remodeling of the extracellular matrix and the apoptosis of excess cells, the inflammatory state gradually decreases.This phase is the longest: after about a year, the scar remodels itself, it is no longer red or rigid, no longer causes pain and it flattens out.

[0008] However, some types of wounds do not heal properly, with the three key stages of the process occurring abnormally, despite the best possible physicochemical and biological conditions being in place. Indeed, the speed and quality of wound healing depend on intrinsic and extrinsic factors. This repair process can therefore be abnormally prolonged depending on: the etiology of the wound; its condition and location; the occurrence of an infection caused by the presence of certain infectious agents such as Staphylococcus aureus Or Pseudomonas aeruginosa;the existence of a pre-existing pathology (such as diabetes, immune deficiency, venous insufficiency, etc.); the external environment; or genetic factors predisposing or not to healing disorders.

[0009] Among these wounds that do not heal properly are ischemic wounds, including ulcers and pressure ulcers. More specifically, such wounds are arterial leg ulcers, mixed leg ulcers, pressure ulcers, and neuroischemic diabetic foot ulcers. Wounds that do not heal properly are more specifically grade 2 and / or 3 ischemic wounds.

[0010] The treatment of ischemic wounds has already been described, including the treatment of diabetic foot. For example, patent FR3066390 describes the use of oligosaccharide compounds to treat arteriopathic diabetic foot ulcers. Edmonds et al.also describe the use of sucrose octasulfate for the treatment of neuroischemic diabetic foot ulcers (Lancet Diabetes Endocrinol 2017), as does Lazaro-Martinez et al. describe the use of a TLC-NOSF dressing for the treatment of neuroischemic diabetic foot ulcers (Journal of Wound Care, Volume 28, June 2019).

[0011] International guidelines also recommend the use of a TLC-NOSF (Technology Lipido-Colloid - Nano-OligoSaccharide Factor) dressing for the treatment of neuroischemic diabetic foot ulcers (Rayman G, et al., Guidelines on use of interventions to enhance healing of chronic foot ulcers in diabetes (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36 Suppl 1:e3283, or National Institute for Health and Care Excellence. UrgoStart for treating leg ulcers and diabetic foot ulcers. January 2019, https: / / www.nice.org.uk / guidance / mtg421.

[0012] Oligosaccharide compounds have also already been described for their use in activating angiogenesis, for example in patent FR3043556.

[0013] Oligosaccharide compounds have also been described for the treatment of neuropathic diabetic foot ulcers (Richard et al., Journal of Wound Care, Vol 21, No. 3, March 2012).

[0014] However, new wound treatments are still desired, as is a better understanding of the healing phenomenon.

[0015] Good oxygenation of wounds, for example, is a factor that promotes healing. On the contrary, ischemia delays healing or even prevents it in the most critical cases, leading to necrosis.

[0016] The present invention is thus more particularly concerned with increasing the oxygenation of the skin for the treatment of grade 2 and / or 3 ischemic wounds, in particular to enable better healing of ischemic wounds.

[0017] Moon KC, Chung HY, Han SK, Jeong SH, Dhong ES. demonstrated a local increase in TcPO 2 in patients with ischemic diabetic foot after injection of adipose-derived stromal vascular fraction (SVF cells) in the study "Possibility of Injecting Adipose-Derived Stromal Vascular Fraction Cells to Accelerate Microcirculation in Ischemic Diabetic Feet: A Pilot Study. Int J Stem Cells. 2019;12(1):107-13". The authors showed an increase in TcPO 2 up to 4 weeks and then a slight decrease.

[0018] On the contrary, the present invention is concerned with increasing the oxygenation of the skin using a synthetic polysulfated oligosaccharide having 1 to 4 ose units, its salts, or its complexes. Such compounds have in particular the advantage of gradually increasing oxygenation ( ie the value of TcPO 2 ) until wound closure and / or treatment of ischemia. Statement of the invention

[0019] The invention is as defined in claims 1 to 10.

[0020] The invention thus relates to a synthetic polysulfated oligosaccharide having 1 to 4 ose units, its salts, or its complexes, for its use in increasing the oxygenation of the skin, said oligosaccharide being sucrose octasulfate.

[0021] According to a first aspect, the invention thus relates to a synthetic polysulfated oligosaccharide having 1 to 4 ose units, its salts, or its complexes, for its use in increasing the oxygenation of the skin during the treatment of grade 2 and / or 3 ischemic wounds, said oligosaccharide being sucrose octasulfate.

[0022] According to a second aspect, the invention also relates to a pharmaceutical composition comprising a synthetic polysulfated oligosaccharide having 1 to 4 ose units, its salts, or its complexes, for its use in increasing the oxygenation of the skin during the treatment of grade 2 and / or 3 ischemic wounds, said oligosaccharide being sucrose octasulfate.

[0023] According to a third aspect, the invention finally relates to a dressing comprising a synthetic polysulfated oligosaccharide having 1 to 4 ose units, its salts, or its complexes, in particular a potassium salt of sucrose octasulfate, for its use in increasing the oxygenation of the skin during the treatment of grade 2 and / or 3 ischemic wounds, said oligosaccharide being sucrose octasulfate. Detailed description of the invention

[0024] Synthetic polysulfated oligosaccharides having 1 to 4 monosaccharide units

[0025] The oligosaccharide according to the invention is sucrose.

[0026] For the purposes of the present invention, the term “polysulfated oligosaccharide” means an oligosaccharide in which all the hydroxyl groups of each ose have been substituted by a sulfate group.

[0027] The polysulfated oligosaccharide used in the context of the present invention is sucrose octasulfate.

[0028] The polysulfated oligosaccharides used in the context of the present invention may be in the form of salts or complexes.

[0029] Examples of salts include alkali metal salts such as sodium, calcium or potassium salts; silver salts; or amino acid salts.

[0030] Examples of complexes include hydroxyaluminum complexes.

[0031] Within the scope of the present invention, particularly preferred compounds are the following: the potassium salt of sucrose octasulfate; the silver salt of sucrose octasulfate; and the hydroxyaluminum complex of sucrose octasulfate, commonly called sucralfate.

[0032] In particular, in the context of the present invention, the polysulfated oligosaccharides used are preferably the potassium salts rather than the aluminum salts of sucrose octasulfate.

[0033] The polysulfated oligosaccharides used in the context of the present invention may be in the form of micronized powder or in solubilized form.

[0034] An example of a polysulfated oligosaccharide used in the context of the present invention is the potassium salt of sucrose octasulfate (known by the abbreviation KSOS), marketed in the product Urgotul ®< Start by URGO Laboratories.

[0035] In the context of the present invention, the polysulfated oligosaccharides used can be associated with phosphate buffered saline (PBS). Composition

[0036] The invention also relates to a pharmaceutical composition comprising a synthetic polysulfated oligosaccharide having 1 to 4 ose units, its salts, or its complexes, for its use in increasing the oxygenation of the skin during the treatment of grade 2 and / or 3 ischemic wounds, said oligosaccharide being sucrose octasulfate.

[0037] According to a particular embodiment, said pharmaceutical composition comprises a synthetic polysulfated oligosaccharide having 1 to 4 ose units, its salts, or its complexes, at a concentration greater than or equal to 70 mg / mL, to increase the oxygenation of the skin during the treatment of ischemic wounds, preferably 100 mg / mL, and more preferably between 100 and 1000 mg / mL, said oligosaccharide being sucrose octasulfate.

[0038] The synthetic polysulfated oligosaccharide used in the pharmaceutical composition according to the invention is sucrose octasulfate, more particularly the potassium salt of sucrose octasulfate. Additional active substance

[0039] Generally speaking, the synthetic polysulfated oligosaccharide compounds according to the invention may be used alone or as a mixture of two or more of them, or in combination with one (or more) other active substance(s), for example in compositions such as those mentioned above.

[0040] Generally, the active ingredients are chosen from antibacterials, antiseptics, painkillers, anti-inflammatories, active ingredients promoting healing, depigmenting agents, antipruritics, UV filters, soothing agents, moisturizing agents, antioxidant agents, and their mixtures.

[0041] Generally, the assets are chosen from: Antibacterials such as Polymyxin B, penicillins (Amoxycillin), clavulanic acid, tetracyclines, Minocycline, chlortetracycline, aminoglycosides, Amikacin, Gentamicin, Neomycin, silver and its salts (Silver sulfadiazine), probiotics, silver salts; Antiseptics such as sodium mercurothiolate, eosin, chlorhexidine, phenylmercury borate, hydrogen peroxide, Dakin's solution, triclosan, biguanide, hexamidine, thymol, Lugol's, Povidone-iodine, Merbromine, Benzalkonium and Benzethonium Chloride, ethanol, isopropanol; painkillers such as Paracetamol, Codeine, Dextropropoxyphene, Tramadol, Morphine and its derivatives, Corticosteroids and derivatives;anti-inflammatory drugs such as glucocorticoids, nonsteroidal anti-inflammatory drugs, aspirin, ibuprofen, ketoprofen, flurbiprofen, diclofenac, aceclofenac, ketorolac, meloxicam, piroxicam, tenoxicam, naproxen, indomethacin, naproxcinod, nimesulide, celecoxib, etoricoxib, parecoxib, rofecoxib, valdecoxib, phenylbutazone, niflumic acid, mefenamic acid;healing active ingredients such as Retinol, Vitamin A, Vitamin E, N-acetyl-hydroxyproline, Centella Asiatica extracts, papain, silicones, essential oils of thyme, niaouli, rosemary and sage, hyaluronic acid, Allantoin, -Hema'tîte (gattefossé), Vitamin C, TEGO Pep 4-17 (evonik), Toniskin (silab), Collageneer (Expanscience), Timecode (Seppic), Gatuline skin repair (gattefossé), Panthenol, PhytoCellTec Alp Rose (Mibelle Biochemistry), Erasyal (libragen), Serilesine (Lipotec), Talapetraka Heterosides (beyer), Stoechiol (codif), macarose (Sensient), Dermaveil (Ichimaru) Pharcos), Phycosaccaride AI (Codif);depigmenting agents such as kojic acid (Kojic Acid SL ®< - Quimasso (Sino Lion)), Arbutin (Olevatin ®< - Quimasso (Sino Lion)), sodium palmitoylpropyl and white water lily extract mixture (Sepicalm ®< - Seppic), undecylenoyl phenylalanine (Sepiwhite ®< - Seppic), antipruritics: hydrocotisone, enoxolone, diphenyhydramine, antihistamine for local application anti H1; moisturizing active ingredients such as xpermoist (lipotec), hyaluronic acid, urea, fatty acids, glycerin, waxes, exossin (unipex); UV filters such as Parsol MCX, Parsol 1789; soothing agents such as chamomile, bisabolol, xanthalene, glycyrrhebenic acid, tanactin (CPN), Calmiskin (Silab); antioxidant agents, such as vitamin E.;

[0042] According to a preferred embodiment, the oligosaccharide compounds according to the invention can be used in combination with an antioxidant agent. Galenic

[0043] The synthetic polysulfated oligosaccharides used in the context of the present invention can be administered topically, and in particular implemented within a galenic formulation, in the form of a composition, such as for example a gel, a solution, an emulsion, a cream, granules, capsules (of variable sizes ranging from nano or micrometer to millimeter), which will allow their application directly to the wound. Alternatively, the compounds used in the context of the present invention can be implemented within a solution for subcutaneous injection.

[0044] If they are used as a mixture of two or more of them or in combination with one or more other active substances, these compounds may be incorporated into the same galenic formulation or into separate galenic formulations.

[0045] Of course, the quantity of synthetic polysulfated oligosaccharides according to the invention used in the galenic formulation is adapted according to the desired kinetics as well as the specific constraints linked to its nature, solubility, heat resistance, etc. Bandage

[0046] Preferably, the synthetic polysulfated oligosaccharide compounds used in the context of the present invention, or a galenic formulation containing them, will be integrated into a dressing.

[0047] For the purposes of this application, dressing means all types of dressings used for the treatment of wounds.

[0048] The invention thus relates to a dressing comprising a synthetic polysulfated oligosaccharide having 1 to 4 ose units, its salts, or its complexes, in particular a potassium salt of sucrose octasulfate, for increasing the oxygenation of the skin during the treatment of grade 2 and / or 3 ischemic wounds, said oligosaccharide being sucrose octasulfate.

[0049] The synthetic polysulfated oligosaccharide compound according to the invention, and in particular the potassium salt of sucrose octasulfate or a galenic formulation containing it, may be incorporated into any element of the structure of a dressing provided that this compound can come directly or indirectly into contact with the surface of the wound.

[0050] Preferably and in order to promote rapid action, this compound (or a galenic formulation containing it) can be incorporated into the layer of the dressing which comes into contact with the wound or deposited on the surface of the dressing which comes into contact with the wound.

[0051] Such deposition techniques are well known to those skilled in the art and some are for example described in patent application WO 2006 / 007814.

[0052] Advantageously, the potassium salt of sucrose octasulfate (or a galenic formulation containing it) can thus be deposited, continuously or discontinuously, on the surface intended to come into contact with the wound: either in liquid form, for example by vaporization of a solution or suspension containing it; or in solid form, for example by sieving a powder containing it.

[0053] The layer or surface coming into contact with the wound may consist, for example, of an absorbent material such as a hydrophilic absorbent polyurethane foam; a textile material such as a compress, such as a non-woven fabric, a film, a fibre veil; an absorbent or non-adhesive adhesive material; an adherent or non-adherent interface structure.

[0054] Typically, a dressing comprises at least one layer or matrix, whether adhesive or not.

[0055] Alternatively, the layer or surface coming into contact with the wound may consist, for example, of a textile weft, preferably made of polyester as described in patent application WO 01 / 70285 or in patent application WO2013 / 093298 on which will be coated, or coated, an elastomeric matrix comprising a synthetic polysulfated oligosaccharide having 1 to 4 ose units, its salts, or its complexes, in particular a potassium salt of sucrose octasulfate, as described in patent application WO2008 / 149035 or in application WO2014 / 009488.

[0056] The synthetic polysulfated oligosaccharide compounds according to the invention, or a galenic formulation containing them, can be incorporated into any element of the structure of a dressing, for example in the matrix.

[0057] The subject of the invention is thus a dressing comprising a textile frame coated with an elastomeric matrix comprising a synthetic polysulfated oligosaccharide having 1 to 4 ose units, its salts, or its complexes, in particular a potassium salt of sucrose octasulfate, for its use in increasing the oxygenation of the skin during the treatment of grade 2 and / or 3 ischemic wounds, said oligosaccharide being sucrose octasulfate.

[0058] According to a preferred embodiment, the invention thus relates to a dressing comprising a synthetic polysulfated oligosaccharide having 1 to 4 ose units, its salts, or its complexes, in particular a potassium salt of sucrose octasulfate for increasing the oxygenation of the skin during the treatment of grade 2 and / or 3 ischemic wounds, said oligosaccharide being sucrose octasulfate, said dressing comprising a textile weave coated with an elastomeric matrix, and said matrix comprising said synthetic polysulfated oligosaccharide.

[0059] Generally speaking, the galenic or the structure of the dressing can be adjusted to obtain a specific release profile of the potassium salt of sucrose octasulfate, rapid or delayed, depending on the needs.

[0060] Of course, the quantity of sucrose octasulfate potassium salt used in the galenic formulation or in the dressing will be adapted according to the desired kinetics as well as the specific constraints linked to its nature, solubility, heat resistance, etc.

[0061] According to a variant of the invention, the synthetic polysulfated oligosaccharide compound according to the invention can be incorporated into an absorbent dressing based on gelling fibers, such as for example the product AQUACEL ®< marketed by the company CONVATEC.

[0062] Very often, when applying these dressings, the caregiver holds them in place with a bandage or covers them with a secondary element such as a second absorbent dressing or a support bandage. It is therefore useful to keep the dressing fixed to the wound so that the caregiver has their hands free to position these secondary elements. Generally speaking, any type of adhesive commonly used in dressings can be used for this purpose.

[0063] In order not to damage healthy tissue or the edges of the wound, particularly when removing the dressing, an adhesive is preferred which has the property of adhering to the skin without adhering to the wound.

[0064] Examples of such an adhesive include adhesives based on silicone or polyurethane elastomers, such as silicone or polyurethane gels, and hydrocolloid adhesives.

[0065] Such hydrocolloid adhesives are in particular made up of an elastomeric matrix based on one or more elastomers chosen from poly(styrene-olefin-styrene) block polymers in association with one or more compounds chosen from plasticizers, such as mineral oils, tackifying resins and, if necessary, antioxidants, into which is incorporated a quantity, preferably small, of hydrocolloids (from 3 to 20% by weight) such as for example sodium carboxymethylcellulose or superabsorbent polymers such as the products marketed under the name LUQUASORB ®< by the company BASF.

[0066] According to a preferred embodiment, the synthetic polysulfated oligosaccharide compounds used in the context of the present invention, or a galenic formulation containing them, will be integrated into a dressing comprising a hydrocolloid adhesive, said polysulfated oligosaccharide being incorporated into said adhesive preferably in an amount of between 1 and 15% by weight, more preferably between 5 and 10% by weight, relative to the weight of the adhesive.

[0067] The formulation of such hydrocolloid adhesives is well known to those skilled in the art and described for example in patent applications FR2783412, FR2392076 and FR2495473.

[0068] The use of an adhesive mesh on the non-woven fabric makes it possible in a particularly advantageous way to reduce or avoid the risk of small fibrils of the textile material coming into contact with the wound and sticking to the tissues, thus causing a painful sensation upon removal, or even an obstacle to the wound healing process.

[0069] According to a preferred embodiment of the present invention, the synthetic polysulfated oligosaccharide compound according to the invention is incorporated into such an adhesive at a concentration compatible with its solubility and its heat resistance.

[0070] Based on these criteria, the synthetic polysulfated oligosaccharide compound according to the invention is preferably used in an amount of between 1 and 15% by weight, and more preferably between 5 and 10% by weight, relative to the total weight of the adhesive.

[0071] If it is desired to increase the absorption of this non-woven dressing, it can be combined with an additional absorbent layer, and preferably an absorbent layer that does not gel, such as in particular a compress such as that used in the URGOTUL ®< Duo or URGOTUL ®< Trio product, an absorbent hydrophilic foam, preferably a hydrophilic polyurethane foam with an absorption capacity greater than that of the non-woven such as that used in the CELLOSORB ®< product.

[0072] According to a preferred embodiment, the synthetic polysulfated oligosaccharide compound according to the invention is incorporated into a non-woven dressing, associated with an additional absorbent layer, and preferably an absorbent layer which does not gel, such as in particular a compress, said oligosaccharide being sucrose octasulfate.

[0073] According to another preferred embodiment, the synthetic polysulfated oligosaccharide compound according to the invention is incorporated into a non-woven dressing, associated with an additional absorbent layer, and preferably an absorbent layer which does not gel, such as in particular an absorbent hydrophilic foam, preferably a hydrophilic polyurethane foam having an absorption capacity greater than that of the non-woven fabric, said oligosaccharide being sucrose octasulfate.

[0074] The nonwoven and the foam can be combined by techniques well known to those skilled in the art, for example by hot calendering using a hot-melt powder based on TPU / polycaprolactone polymers.

[0075] This technique is commonly used for bonding non-woven fabrics intended for the medical market.

[0076] Finally, this foam or non-woven fabric (when used alone) can be covered with a support to protect the wound from the outside.

[0077] This support can be larger than the other layers and made adhesive continuously or discontinuously on its side coming into contact with the wound in order to optimize the support of the dressing during use, in particular if the wound is located on non-flat areas of the body.

[0078] This support and its adhesive are preferably impermeable to fluids but very permeable to water vapor in order to allow optimal management of exudates absorbed by the dressing and avoid maceration problems.

[0079] Such supports are well known to those skilled in the art and consist, for example, of breathable and waterproof films such as polyurethane films, foam / film or non-woven / film complexes. Additives

[0080] In addition to the active agents, the synthetic polysulfated oligosaccharide compounds according to the invention may be used in combination with one (or more) additives commonly used in the preparation of dressings. These additives may in particular be chosen from perfumes, preservatives, vitamins, glycerin, citric acid, etc. Therapeutic application

[0081] The synthetic polysulfated oligosaccharide compound according to the invention is used to increase skin oxygenation during the treatment of grade 2 and / or 3 ischemic wounds.

[0082] According to one embodiment, the invention relates to a synthetic polysulfated oligosaccharide having 1 to 4 ose units, its salts, or its complexes, for its use in increasing the oxygenation of the skin during the treatment of grade 2 and / or 3 ischemic wounds, said oligosaccharide being sucrose octasulfate.

[0083] Preferably, the oligosaccharide for its use according to the invention is used at a concentration greater than or equal to 70 mg / mL, preferably 100 mg / mL, and more preferably between 100 and 1000 mg / mL.

[0084] According to the invention, the term "increasing the oxygenation of the skin" means locally increasing, directly at the level of the wound, the oxygen concentration, with the aim of promoting healing.

[0085] Skin oxygenation is determined by measuring TcPO 2 (i.e., transcutaneous oxygen pressure, in other words, the pressure of oxygen diffusing through the skin at the wound site). In the term "TcPO 2", Tc refers to the term "transcutaneous", P to "Pressure" and O 2 to oxygen.

[0086] TcPO 2 is preferably measured using a TCM400 device (Radiometer), placing the electrodes in contact with the wound, as described in the examples or in the publication Izzo V, et al., Rearfoot Transcutaneous Oximetry is a Useful Tool to Highlight Ischemia of the Heel. Cardiovasc Intervent Radiol. 2017;40(1):120-4.

[0087] According to the invention, TcPO2 is preferably measured on the first day of treatment, then monthly until the wound has healed.

[0088] According to one embodiment, the oligosaccharide for its use according to the invention allows an increase in TcPO 2 of at least 10 mm Hg between the first day of treatment and healing of the wound, more particularly the treatment of grade 2 and / or 3 ischemic wounds, said oligosaccharide being sucrose octasulfate.

[0089] According to the invention, "ischemic wounds" means wounds resulting from a reduction in arterial blood supply. Ischemic wounds are classified into 3 categories: wounds with low ischemia (grade 1), wounds with moderate ischemia (grade 2), and finally wounds with critical ischemia (grade 3). The distinction between these different grades is established by the following classification, described in the publication "The Society for Vascular Surgery Lower Extremity Threatened Limb Classification System: Risk stratification based on Wound, Ischemia, and foot Infection (WIfI)", Joseph L. Mills Sr. MD, Michael S. Conte MD et al., Journal of Vascular Surgery.

[0090] According to the invention, "ischemia" means a defect in the arterial blood supply to a tissue (for example a wound), and a defect in the oxygenation of said tissue.

[0091] The present invention is directed to grade 2 and / or 3 ischemic wounds. The present invention herein aims to target wounds exhibiting moderate or critical ischemia, in order to treat the wound, treat the ischemia of said wound or reduce the ischemia of said wound. In other words, according to this embodiment, the present invention is directed to ischemic wounds exhibiting a TcPO 2 value of less than 30 mm Hg, up to a value of less than or equal to 39 mm Hg.

[0092] According to one embodiment, "grade 2 and / or 3 ischemic wounds" means grade 2 ischemic wounds and / or grade 3 ischemic wounds and / or grade 2 and 3 ischemic wounds. According to a preferred embodiment, these are grade 2 and 3 ischemic wounds.

[0093] According to the invention, the reduction of wound ischemia is understood more particularly to mean the progression of a grade 3 ischemic wound to grade 2, and / or the progression of a grade 2 ischemic wound to grade 1. The present invention consists here of a treatment of wounds at an advanced, or even very advanced, stage, and in particular by targeting ischemia. The reduction of ischemia in fact makes it possible to promote the progression of the wound towards healing.

[0094] According to the invention, the ischemic wounds are chosen from arterial leg ulcers, mixed leg ulcers, pressure ulcers, and neuroischemic diabetic foot ulcers. According to a particular embodiment, the ischemic wounds are chosen from arterial leg ulcers, mixed leg ulcers, and pressure ulcers. A diabetic foot ulcer (DFU) is defined as "a deep wound located below the ankle in a diabetic patient, regardless of its duration" (FID, 2005). Indeed, the primary cause of the lack of healing of these diabetic wounds is linked to exacerbated glucose bioavailability. This induces numerous physiological and metabolic changes, such as thickening of the skin, significant oxidative stress which can lead to neuropathy or ischemia which can be mild, moderate or critical.Ischemia is therefore a major risk factor for delayed healing of diabetic foot ulcers.

[0095] According to a particular embodiment, the ischemic wounds are selected from among grade 2 and / or 3 ischemic arterial leg ulcer, grade 2 and / or 3 ischemic mixed leg ulcer, grade 2 and / or 3 ischemic decubitus ulcer, and grade 2 and / or 3 ischemic neuroischemic diabetic foot ulcer. According to an even more particular embodiment, the ischemic wounds are selected from among grade 2 and / or 3 ischemic arterial leg ulcer, grade 2 and / or 3 ischemic mixed leg ulcer, and grade 2 and / or 3 ischemic decubitus ulcer.

[0096] According to a particular embodiment, the diabetic foot ulcer treated within the framework of the present application has a dimension less than 5 cm 2< , that is to say that the wound fits within a circle whose area is 5 cm 2< .

[0097] According to a further preferred embodiment, the diabetic foot ulcer treated within the framework of the present application is not recalcitrant, that is to say it has formed less than 6 months ago.

[0098] According to a particular embodiment, the neuroischemic diabetic foot ulcer which is the subject of the present application has: an Ankle-Body Pressure Index (ABPI) less than or equal to 0.9, or an Ankle-Body Pressure Index (ABPI) greater than 0.9 associated with a Toe-Body Pressure Index (TBPI) less than or equal to 0.7.

[0099] An arterial leg ulcer is defined as "a chronic leg wound of vascular origin that has not healed for more than one month." This condition is characterized by a loss of skin substance in the epidermis and dermis, directly due to ischemia due to a lack of arterial perfusion of the limb.

[0100] According to a particular embodiment, the arterial leg ulcer has an Ankle Systolic Pressure Index (ASPI) of between 0.6 and 0.8.

[0101] A mixed leg ulcer is defined as "a chronic wound of the leg of venous and vascular origin, which has not healed for more than one month." This pathology is characterized by a loss of skin substance of the epidermis and dermis, directly due to ischemia due to a lack of venous and arterial perfusion of the limb.

[0102] According to a particular embodiment, the arterial leg ulcer has an Ankle Systolic Pressure Index (ASPI) of between 0.6 and 0.8.

[0103] A pressure ulcer is defined as "a chronic wound caused by constant pressure." It affects the epidermis, dermis, and bones. Particularly sensitive areas of skin are those located directly on the surface of bones. This condition is characterized by ischemic necrosis. Pressure ulcers are classified into four stages of increasing severity: Stage 1: Permanent redness and sometimes a feeling of warmth in the affected area of ​​skin, the skin is intact. Stage 2: Formation of skin blisters, scratching of the epidermis and sometimes a superficial wound. Stage 3: The epidermis, the dermis and the connective tissue are affected. A deep wound appears. Stage 4: Deep wound extending to the muscle and bone tissue.

[0104] The activity of the synthetic polysulfated oligosaccharides according to the invention has been demonstrated in the following non-limiting examples. Examples Example 1 : Increased skin oxygenation in the treatment of neuroischemic diabetic foot ulcers

[0105] The aim of this study was to evaluate the effect of TcPO 2 (mm Hg) values ​​in the use of a sucrose octasulfate-based dressing during the healing process of neuroischemic diabetic foot ulcers. 1. Materials & Methods Patients

[0106] The study was conducted on 11 patients. The inclusion criteria for patients in the study were as follows: patients over 18 years old diagnosed with diabetes mellitustype 1 or 2, with a non-infected neuroischemic diabetic foot ulcer of grade IC or IIC, as defined by the University of Texas Diabetic Wound Classification System (Armstrong DG, Lavery LA, Harkless LB. Validation of a diabetic wound classification system. The contribution of depth, infection, and ischemia to risk of amputation. Diabetes Care. 1998;21(5):855-9), glycemic control confirmed by an HbA 1c level ≤ 10% (85.8 mmol / mol) within the previous three months. These patients were candidates to begin treatment with a sucrose octasulfate dressing, with a wound area between 1 and 30 cm 2 < .

[0107] Patients with critical limb ischemia, end-stage renal disease or dialysis, edema due to vascular, renal or cardiac disease, patients with chronic obstructive pulmonary disease (COPD) that may alter systemic oxygen saturation, patients with a stroke within the last three months, acute Charcot foot, and those with surgical revascularization within the three months prior to study entry were excluded. Patient assessment

[0108] Neuropathy was confirmed using a 10 g Semmes-Weinstein monofilament and / or biothesiometer (Me.Te.Da. srl, Via Silvio Pellico, 4, 63074 San Benedetto del Tronto, Italy) (Armstrong DG, Lavery LA, Harkless LB. Validation of a diabetic wound classification system. The contribution of depth, infection, and ischemia to risk of amputation. Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA.

[0109] Neuroischemic patients were defined as having an Ankle-Brace Index (ABPI) less than or equal to 0.9; or an Ankle-Brace Index (ABPI) greater than 0.9 associated with a Toe-Brace Index (TBI) less than or equal to 0.7.

[0110] TcPO 2 values ​​were measured using the TCM400 measuring device (Radiometer, Copenhagen, Denmark), placing the electrode on the angiosome of the posterior tibial artery or dorsalis pedis depending on the location of the ulcer (Izzo et al. ) . Patients were placed in a supine position for the 10-minute examination and asked not to move or talk. After calibration, the electrode was placed at the dorsalis pedis artery in all diabetic foot ulcers located in the toes or forefoot and at the posterior tibial artery in patients with diabetic foot ulcers in the midfoot or hindfoot. TcPO 2 values ​​were assessed on day 0, monthly, and on the day of wound closure / healing. Wound Assessment

[0111] Wound healing was assessed based on improvements in the Wollina scoring system (Wollina U, et al., Some effects of a topical collagen-based matrix on the microcirculation and wound healing in patients with chronic venous leg ulcers: preliminary observations. Int J Low Extrem Wounds. 2005;4(4):214-24), and wound area surface area at day 0 and monthly until 20 weeks of follow-up or healing. Healing was defined as complete epithelialization without any drainage, confirmed at least 10 days after wound closure was first noted (Edmonds M, et al., Sucrose octasulfate dressing versus control dressing in patients with neuroischaemic diabetic foot ulcers (Explorer): an international, multicenter, double-blind, randomized, controlled trial. Lancet Diabetes Endocrinol. 2018;6(3):186-96)).

[0112] All patients received standard care consisting of ulcer debridement and proper offloading following the recommendations of the IWGDF guidelines (Bus SA, et al., Guidelines on offloading foot ulcers in persons with diabetes (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36 Suppl 1:e3274.). Diabetic foot ulcers were dressed with a sucrose octasulfate dressing (UrgoStart Contact, 10 × 10 cm, Laboratoires Urgo Medical, Chenôve, France). This is a non-adherent, non-occlusive dressing with a soft contact layer composed of a polyester mesh impregnated with a lipidocolloid matrix containing sucrose octasulfate potassium salt (NOSF: nano-oligosaccharide factor). A senior healthcare provider monitored all patients' care on the ward by applying the dressing twice a week until the end of the study.Additionally, the same clinician performed follow-up on a monthly basis to record study variables. Statistical analysis

[0113] The assumption of normality of all continuous variables was checked using the Shapiro-Wilk test. Normally distributed variables (Shapiro-Wilk test with p > 0.05) were reported as mean and standard deviation.

[0114] Student's t-test for paired samples was used to explore differences in TcPO 2 values, Wollina score, and wound area within the octasulfate dressing treatment due to the normal distribution of the variables.

[0115] All statistical analyses were performed using SPSS Statistics for Mac OS version 25.0 (SPSS, Chicago, IL, USA). P values ​​<0.05 were considered statistically significant, with 95% confidence intervals. 2. Results

[0116] A total of 11 patients were included in this pilot study and followed up until ulcer healing. Demographic characteristics, diabetes mellitus, and foot complications at baseline are presented in Table 2. [Table 2]

[0117] Table 2. Characteristics of the 11 study patients (Abbreviations: SD, standard deviation; TcPO2, transcutaneous oxygen pressure) Features Patients (N=11) Male, n (%) 8 (72.7 %) Female, n (%) 3 (27.3 %) Mean age ± SD (years) 61.91 + / - 8.87 Body mass index (kg / cm 2 < ), mean ± SD 30.05 + / - 4.98 Diabetes mellitus type 1, n (%) 3 (27.3 %) Diabetes mellitus type 2, n (%) 8 (72.7 %) Glycated hemoglobin (%), mean ± SD 7.62 + / - 1.15 Duration of diabetes mellitus (year), mean ± SD 26.36 + / - 13.60 Complications of diabetes mellitus Retinopathy, n (%) 5 (54.5 %) Nephropathy, n (%) 2 (18.2 %) Heart disease, n (%) 2 (18.2 %) Hypertension, n (%) 8 (72.7 %) Current systemic treatments Antihypertensive, n (%) 8 (72.7%) Lipid-lowering, n (%) 10 (90.9%) Antiplatelet, n (%) 9 (81.8%) Smoker, n (%) 4 (36.4 %) History of diabetic foot ulcer, n (%) 9 (81.8 %) Previous minor amputation, n (%) 7(63.6 %) Presence of dorsalis pedis pulse, n (%) 2 (18.2 %) Presence of a posterior tibial artery pulse, n (%) 3 (27.3 %) Ankle-brachial pressure index, mean ± SD 1.19 + / - 0.28 Brachial pressure index at the toe, mean ± SD 0.60 + / - 0.11 Toe systolic pressure (mm Hg), mean ± SD 72.62 + / - 9.60 TcPO 2 Day 0 (mm Hg), mean ± SD 33.54 + / - 11.16

[0118] Four diabetic foot ulcers (36.4%) were located in the hallux, two (18.2%) under the first metatarsal head (MTH), one (9.1%) under the second MTH, one (9.1%) under the third MTH, one (9.1%) under the fifth MTH, one (9.1%) in the midfoot, and finally, one (9.1%) in the heel. The characteristics of the wounds are presented in Table 3. [Table 3]

[0119] Table 3 Wound characteristics (Abbreviations: SD, standard deviation; IQR, interquartile range) Wound characteristics Patients (N=11) Wound duration (week), median [IQR] 8 [48 - 2] Wound area (cm 2 < ), median [IQR] 1.30 [1.60 - 1] Mean Wollina score ± SD 4.18 + / - 1.72 Texas Classification, IC: Ischemia but no infection, superficial wound, n (%) 6 (54.5%) IIC: Ischemia but no infection, wound penetrating tendons, capsule, n (%) 5 (45.5%) Condition of the perilesional skin Hyperkeratosis, n (%) 6 (54.5%) Macerated, n (%) 3 (27.3%) Detachment, n (%) 2 (18.2%) Amount of exudate Low, n (%) 4 (36.4%) Mean, n (%) 5 (45.5%) High, n (%) 2 (18.2%) Wound bed tissue Granulation tissue, n (%) 7 (63.6%) Soft tissue, n (%) 2 (18.2%) Mixed (granulation and soft), n (%) 2 (18.2%)

[0120] The frequency of tissue debridement was considered necessary in each patient. Patients received treatment with an offloading device depending on the location of the ulcer (Table 4). [Table 4]

[0121] Table 4. Wound interventions during the follow-up period Wound interventions Patients (N=11) Discharge device described Non-removable knee-height discharge device, n (%) 5 (45.5%) Post-surgical shoe device, n (%) 5 (45.5%) Heel relief device, n (%) 1(9.1%) Wound debridement Mechanics, n (%) 3 (27.3%) Surgery, n (%) 8 (72.7%) TcPO 2 - electrode location Dorsalis pedis, n (%) 9 (81.8%) Posterior tibial, n (%) 2 (18.2%) Secondary dressing used Gauze, n (%) 6 (54.5%) Foam, n (%) 5 (45.5%)

[0122] All patients included in the study recovered within a median of 8 weeks IQR [8 - 5].

[0123] TcPO 2 values ​​after local treatment with sucrose octasulfate dressing showed a (statistically significant) increase between day 0 (33.54 + / - 11.16 mm Hg) and the day of wound closure (45.27 + / - 13.62 mm Hg), p-value <0.016 (Table 5). [Table 5]

[0124] Table 5. Differences in TcPO 2 values ​​in patients' feet after application of a sucrose octasulfate-containing dressing (N = 11) (All comparisons were made with respect to TcPO 2 values ​​on day 0. P < 0.05 indicates a statistically significant difference) Duration Patients (N=11) P - value Day 0 33.54 + / - 11.16 - Week 4 38.09 + / - 13.53 .303 Week 8 43.50 + / - 13.65 .056 Wound closure 45.27 + / - 13.62 .016

[0125] During the follow-up period, Wollina wound scores showed significant improvement, from a mean score of 4.2 + / - 1.7 points at day 0 to 5.4 + / - 1.3 points at the end of the study (N = 11, p = 0.004).

[0126] Finally, the median wound area at day 0 was 1.30 IQR [1.60 - 1] cm 2< and 0.5 IQR [1.1 - 0.1] cm 2< at week 4, with a significant reduction in wound area during the follow-up period (N = 11, p < .001).

[0127] These results therefore show that a synthetic polysulfated oligosaccharide having 1 to 4 ose units, its salts, or its complexes, (more particularly sucrose octasulfate) makes it possible to increase the oxygenation of the skin during the treatment of ischemic wounds. Example 2 : Increased skin oxygenation in the treatment of neuroischemic diabetic foot ulcers

[0128] The study of Example 1 has been completed, and the results are presented in Table 6. [Table 6]

[0129] Table 6. Differences in TcPO 2 values ​​in patients' feet after application of a sucrose octasulfate-containing dressing (N = 34) (All comparisons were made with respect to TcPO 2 values ​​on day 0. P < 0.05 indicates a statistically significant difference) Duration Patients (N=34) P - value Day 0 31.29 ± 9.61 - Week 4 37.55 ± 12.96 0.004 Week 8 37.26 ± 14.98 .04 Week 12 46.14± 9.33 0.04 Wound closure 42.87 ± 12.16 .007

[0130] During the follow-up period, Wollina wound scores showed significant improvement, from a mean score of 3.95 + / - 1.94 points at day 0 to 5.75 + / - 0.95 points at the end of the study (p = 0.003).

[0131] Finally, the median wound area at day 0 was 1.40 IQR [1.70 - 1.2] cm 2< and 0.2 IQR [1.1 - 0.1] cm 2< at week 4, with a significant reduction in wound area during the follow-up period (p < .001). Example 3 : Evolution of skin oxygenation according to the grade of the ischemic wound

[0132] The 34 patients in Example 2 were separated according to the ischemic wound classification, as shown in Table 1. The change in TcPO 2 values ​​at the patients' feet after application of a dressing containing sucrose octasulfate was measured. Statistical analysis was performed as shown in Example 1.

[0133] The results are presented in Table 7. [Table 7]

[0134] Table 7 . Differences in TcPO 2 values ​​according to ischemic wound classification. Classification of ischemic wound TcPO 2 (Day 0) TcPO 2 (healing) ΔTcPO 2 P - value 0 - - - - 1 45,33± 4,27 51,22 ± 8,46 5,89 0.133 2 32,81 ± 2,27 44,27 ± 10,52 11,46 0.005 3 23,14 ± 3,05 36,57 ± 11,96 13,43 0.001

[0135] The results show that on the day of healing, grade 3 ischemic wounds (TcPO 2 < 30 mm Hg) evolved into grade 2 ischemic wounds (TcPO 2 < 30-39 mm Hg).

[0136] The results also show that grade 2 ischemic wounds (TcPO 2 < 30-39 mm Hg) progressed to grade 1 ischemic wounds (TcPO 2 < 40-59 mm Hg).

[0137] In contrast, grade 1 ischemic wounds remain classified as grade 1 ischemic wounds (TcPO 2 < 40-59 mm Hg).

[0138] These results therefore show the particular interest conferred by the invention for the treatment of grade 2 and / or 3 ischemic wounds. The oxygenation of grade 2 and 3 ischemic wounds is in fact improved by more than 10 mm Hg between the first day of treatment and healing, which is more than double compared with the increase in oxygenation of grade 1 ischemic wounds.

Claims

1. Synthetic polysulfated oligosaccharide having 1 to 4 monosaccharide units, salts thereof, or complexes thereof, for use in increasing the oxygenation of the skin when treating grade 2 and / or 3 ischaemic wounds, said oligosaccharide being sucrose octasulfate and said grades being defined in Table 1:

2. Oligosaccharide for use according to claim 1, characterised in that the ischaemic wounds are selected from arterial leg ulcer, mixed leg ulcer, pressure ulcer, and neuroischaemic diabetic foot ulcer.

3. Oligosaccharide for use according to any one of the preceding claims, characterised in that the ischaemic wounds are selected from arterial leg ulcer, mixed leg ulcer, and decubitus ulcer.

4. Oligosaccharide for use according to any one of the preceding claims, characterised in that its concentration is greater than or equal to 70 mg / mL, preferably 100 mg / mL, and more preferably between 100 and 1000 mg / mL.

5. Oligosaccharide for use according to any one of the preceding claims, characterised in that it is selected from: - the potassium salt of sucrose octasulfate; - the silver salt of sucrose octasulfate; and - the hydroxyaluminium complex of sucrose octasulfate.

6. Oligosaccharide for use according to any one of the preceding claims, characterised in that it is the potassium salt of sucrose octasulfate.

7. Oligosaccharide for use according to any one of the preceding claims, characterised in that it is used in the form of a composition such as a gel, a solution, an emulsion, a cream, granules or capsules allowing direct application to the wound.

8. Pharmaceutical composition comprising a synthetic polysulfated oligosaccharide having 1 to 4 monosaccharide units, salts thereof, or complexes thereof, for use in increasing the oxygenation of the skin when treating grade 2 and / or 3 ischaemic wounds, said oligosaccharide being sucrose octasulfate and said grades being defined in Table 1:

9. Dressing comprising a synthetic polysulfated oligosaccharide having 1 to 4 sugar units, salts thereof, or complexes thereof, for use in increasing the oxygenation of the skin when treating grade 2 and / or 3 ischaemic wounds, said oligosaccharide being sucrose octasulfate and said grades being defined in Table 1:

10. Dressing for use according to claim 9, comprising a textile weft coated with an elastomeric matrix, said matrix comprising said synthetic polysulfated oligosaccharide.